Inhaled particles play a major role in inducing or exacerbating respiratory diseases. The acinar region, with its enormously large surface area and very thin and delicate blood/gas barrier, is particularly vulnerable to the damaging effects of depositing particles. An essential step in understanding toxic particle exposure associated processes in the pulmonary acinus, as well as targeted drug delivery by aerosol inhalation, is to characterize deposition and to elucidate the mechanisms involved. Previously we have laid the foundation of a new conceptual framework for acinar deposition studies by establishing theoretically and experimentally that, contrary to a commonly held view, acinar gas flow can be kinematically irreversible, and by showing that chaotic mixing, manifested by stretching and folding patterns, can be a major contributor to aerosol deposition. This proposed project builds on these achievements and aims to study the specific mechanisms of the stretch and fold kinematics. Our main hypothesis is that tidal air front evolves into an enormously stretched layer upon inhalation which drapes the inner surface of the acinar airways, thus bringing airborne aerosols very close to the alveolar septal surface and promoting their deposition. During exhalation, folding of the previously stretched layer leads to lateral transport of aerosols, also significantly contributing to the deposition process. This novel hypothesis will be rigorously tested in three specific aims: Aim 1 addresses computationally detailed mechanisms of draping and folding in the acinar structure. Aim 2 investigates analytically the chaotic mixing, draping and folding induced by asynchronous flows in multiply branching structures. Aim 3 addresses experimentally the behavior of an inhaled bolus of aerosol with various ventilatory maneuvers, as well as visualizing and quantifying the extent of draping and folding. These experiments will be performed in normal rats and in a rat model of emphysema. Our overall goal is to identify, through the combination of these theoretical and experimental studies, the important mechanisms of aerosol deposition governed by airflow kinematics in the unique structure of the lung periphery and thereby to advance our understanding of the risks of exposure to aerosolized pollutants and the positive potential of targeted therapeutic drug delivery.